AAC · Using aminoglycoside acetyltransferases and synthetic acyl-coenzyme A derivatives for the development of novel N-acylated antibiotics analogs

Using aminoglycoside acetyltransferases and synthetic acyl-coenzyme A derivatives for the development of novel N-acylated antibiotics analogs

Executive Summary: The Fridman laboratory is engaged in the use of organic chemistry, especially carbohydrate chemistry, to solve key biological and medicinal problems in the interface of Chemistry and Biology with Medicinal applications. Our current research covers three major topics: I) rational design of membrane targeting antibiotics, II) development of chemoenzymatic and chemical approaches to circumvent the action of certain resistance mechanisms to aminoglycoside antibiotics, II) structure-function studies and rational design of novel antitumor agents. This Marie Curie re-integration project program focused on aminoglycosides which are broad-spectrum antibiotics commonly used for the treatment of serious bacterial infections. Decades of clinical use have led to the widespread emergence of bacterial resistance to this family of drugs limiting their efficacy in the clinic. A common mode of bacterial resistance evolved through the acquisition of enzymes that chemically modify aminoglycosides and lead to their deactivation. In this study the Fridman group used several members of a family of aminoglycoside-modifying enzymes that evolved in bacteria to deactivate the aminoglycosides for the preparation of new generations of these antibiotics. The enzymes that were chosen proved useful for the preparation of a variety of new aminoglycoside antibiotics. Our chemoenzymatic approach was used for the generation of sufficient amounts of compounds for a qualitative screen for antibacterial activity. In bacteria with resistance to aminoglycosides, the effect of some of the new analogues was dramatic: Good antibacterial activity was retained although the activity of the parent drug was compromised. In this study we demonstrated that, our approach for the development of novel aminoglycosides that are not susceptible to several drug resistance pathways and, as such, maintain their antibacterial activity against certain aminoglycoside resistant bacteria is indeed feasible. The aminoglycoside antibiotics project was also extended to an additional aspect: Development of bacterial membrane targeting antibiotics. To date, disruption bacterial membranes has been poorly exploited as a strategy for the development of antibiotics. The Fridman research group has focused on aminoglycoside antibiotic tobramycin, and synthesized several novel families of bacterial membrane disrupting antibiotics. Through microbiological tests as well as confocal microscopy, we found evidence that these compounds target bacterial membranes. The scientific results of this project led to seven scientific publications in several top journals. The Fridman group is now one of the leading research groups in the fields of membrane targeting antimicrobial agents development and study. On July 2013, Dr. Fridman obtained his tenure from the Tel Aviv University School of Chemistry and successfully completed his academic re-integration procces in Tel Aviv University. The Fridman group is now an established research group with several studies in the fields of Chemical Biology and Medicinal Chemistry. The Marie Curie Reintegration program had key role at creating both the financial and scientific foundations for the succsessful establishment of the Fridman group during its first years.

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